NM_001197104.2:c.5630C>T

Variant names:

• chr11-118496333-C-T
• rs782094920
• NM_001197104.2:c.5630C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4 BP6_Very_Strong BS2

The NM_001197104.2(KMT2A):​c.5630C>T​(p.Ala1877Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,613,306 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A1877A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (1 hom.)
• Consequence: KMT2A NM_001197104.2 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.45
• Publications: 2 publications found

Genes affected

KMT2A (HGNC:7132): (lysine methyltransferase 2A) This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

KMT2A Gene-Disease associations (from GenCC):

• Wiedemann-Steiner syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.31749985).
• BP6: Variant 11-118496333-C-T is Benign according to our data. Variant chr11-118496333-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 562030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAdExome4 at 16 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197104.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2A	NM_001197104.2	MANE Select	c.5630C>T	p.Ala1877Val	missense	Exon 20 of 36	NP_001184033.1	Q03164-3
	KMT2A	NM_001412597.1		c.5720C>T	p.Ala1907Val	missense	Exon 21 of 37	NP_001399526.1	A0AA34QVI8
	KMT2A	NM_005933.4		c.5621C>T	p.Ala1874Val	missense	Exon 20 of 36	NP_005924.2	Q03164-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2A	ENST00000534358.8	TSL:1 MANE Select	c.5630C>T	p.Ala1877Val	missense	Exon 20 of 36	ENSP00000436786.2	Q03164-3
	KMT2A	ENST00000389506.10	TSL:1	c.5621C>T	p.Ala1874Val	missense	Exon 20 of 36	ENSP00000374157.5	Q03164-1
	KMT2A	ENST00000531904.7	TSL:2	c.5729C>T	p.Ala1910Val	missense	Exon 21 of 37	ENSP00000432391.3	E9PR05

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151978 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000199 AC: 5 AN: 251470 AF XY: 0.0000221

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000109 AC: 16 AN: 1461328 Hom.: 1 Cov.: 30 AF XY: 0.0000124 AC XY: 9 AN XY: 726976

African (AFR) AF: 0.0000299 AC: 1 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39684

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53386

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111586

Other (OTH) AF: 0.00 AC: 0 AN: 60360

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151978 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74226

African (AFR) AF: 0.0000483 AC: 2 AN: 41384

American (AMR) AF: 0.00 AC: 0 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Intellectual disability (1)
-	-	1	KMT2A-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.069	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Benign	0.16
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.057	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.53	N
PhyloP100		3.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.46
Sift	Benign	0.13	T
Sift4G	Benign	0.15	T
Polyphen		0.90	P
Vest4		0.46
MutPred		0.52		Gain of sheet (P = 0.0344)
MVP		0.80
MPC		1.0
ClinPred		0.089	T
GERP RS		5.4
Varity_R		0.14
gMVP		0.49
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs782094920; hg19: chr11-118367048; COSMIC: COSV100629035; COSMIC: COSV100629035;